Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Fleury‐Feith, Jocelyne; Lecomte, Conrad; Renier, Annie; Matrat, M.; Kheuang, Laurence; Abramowski, Vincent; Levy, F.; Janin, Anne; Giovannini, Marco; Jaurand, Marie‐Claude

doi:10.1038/sj.onc.1206593

Cited by 92 publications

(89 citation statements)

References 33 publications

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“…Moreover, Nf2( þ /À) mice exhibit a wide range of highly invasive and metastatic tumors (McClatchey et al, 1998). Finally, Nf2( þ /À) mice exposed to asbestos exhibit accelerated formation of highly malignant mesothelial tumors (Fleury-Feith et al, 2003;Altomare et al, 2005). Our data suggest that NF2 inactivation plays an important role in cell invasiveness, as demonstrated by both 'loss-of-function' studies on primary MEFs and 'gain-of-function' experiments with NF2-deficient MM cells.…”

Section: Discussionmentioning

confidence: 51%

“…Although Nf2-null mice die during embryonic development, mice heterozygous for a mutation at the Nf2 locus develop a range of highly invasive and metastatic tumors (McClatchey et al, 1998). Moreover, Nf2 ( þ /À) mice are more susceptible to the MM development after exposure to asbestos than their wild-type counterparts (Fleury-Feith et al, 2003;Altomare et al, 2005). In addition, the tumors that arise in these mice exhibit highly invasive properties, often with prominent vascularity and/or spreading to the surrounding tissues .…”

Section: Introductionmentioning

confidence: 99%

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Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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“…Both CDKN2A and NF2 encode for tumorsuppressor genes and when either gene is inactivated within a murine model, the mice rarely develop mesothelioma. 28,42 However, concomitant loss of both CDKN2A and NF2 results in a high incidence of mesothelioma with a relatively short latency. 42 Taken together, these observations indicate alterations in both CDKN2A and NF2 define an aggressive subtype of mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

“…16,26 Hemizygous loss of NF2 is associated with increased mesothelioma proliferation, invasiveness, spreading, and migration. [26][27][28] Mutations in the nuclear deubiquitinase, BAP1, result in either complete absence of protein expression or cytoplasmic sequestration of BAP1, which can be detected by immunohistochemistry, in 27-67% of pleural mesotheliomas. 18,29,30 In contrast to CDKN2A and NF2 alterations, loss of BAP1 protein expression portends improved prognosis for patients with pleural mesothelioma.…”

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confidence: 99%

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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“…The tumor suppressor neurofibromin 2 is encoded by the NF2 gene, located on chromosome 22q12. Mutations in NF2 are found in ~40% of MPMs, and heterozygous loss of NF2 is identified in ~74% of MPMs (6,7). Mutations are rare in the TP53 and RAS genes, which are frequently present in epithelial solid tumors (8,9).…”

Section: Introductionmentioning

confidence: 99%

DNA copy number gains in malignant pleural mesothelioma

et al. 2015

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Abstract. Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different. IntroductionMalignant pleural mesothelioma (MPM) is a tumor derived from the mesothelial cells lining the pleural spaces. MPM has highly invasive and aggressive clinical characteristics. Approximately 80% of MPM patients have a history of occupational asbestos exposure, which is considered to be a risk factor for the development of the disease (1). The molecular pathogenesis of MPM is not well understood. The most common mutations in MPMs are losses in 9p21, 1p36, 14q32 and 22q12, and gains in 5p, 7p and 8q24, which have been detected by comparative genomic hybridization analysis (2,3). Homozygous deletion of the 9p21 locus encoding two critical cyclin-dependent kinase inhibitors, p16INK4a and p15 INK4b , have been reported in up to 80% of MPMs, and this mutation may be of diagnostic utility (4,5). The tumor suppressor neurofibromin 2 is encoded by the NF2 gene, located on chromosome 22q12. Mutations in NF2 are found in ~40% of MPMs, and heterozygous loss of NF2 is identified in ~74% of MPMs (6,7). Mutations are rare in the TP53 and RAS genes, which are frequently present in epithelial solid tumors (8,9). Epigenetic alterations, such as DNA methylation, have been found in MPMs, which have a different profile compared with lung cancer (10-12). MPMs, particularly of the epithelioid subtype, may be hard to differentiate from adenocarcinoma arising in the lung periphery, and epidemiological evidence indicates that asbestos and smoking are shared risk factors for these diseases (2,13,14). Currently, the differential diagnosis of MM is based on a range of morphological analyses, including a combination of histological and immunohistochemical staining, and electron microscopy (13,15,16).Cytogenetic studies have been performed on MPMs and adenocarcinomas arising in the lung periphery, however, no chromosomal aberra...

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Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Cited by 92 publications

References 33 publications

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

DNA copy number gains in malignant pleural mesothelioma

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